This application claims the benefit of Brazilian Patent Application No. PI9904931-7, Filed Oct. 18, 1999.
The invention relates to the inhibition of formation of potential amyloidoses, the inhibition of development of existing amyloidoses, and the dissolution of existing amyloidoses, by the administration of particular compounds and compositions comprising such compounds.
Amyloidoses are pathological conditions characterized by the presence of amyloid deposits. Currently a number of amyloidogenic proteins or peptides (derived from different precursor molecules) are known to be involved in diseases as diverse as diabetes, rheumatoid arthritis, Alzheimer""s disease, and others. The elimination of factors that promote the formation or development of amyloid deposits can result in the loss of existing deposits and the functional recovery of the affected tissues (Kisilevsky et al., Crit. Rev. Biochem. Mol. Biol., 32, 361-404, 1997).
U.S. Pat. No. 5,859,001 describes compositions and methods for protecting against the death of central nervous system cells and also relates to the stimulation of neuronal survival in individuals with neurodegenerative conditions. According to this patent, neuroprotection can be provided to a cell population via the use of non-estrogenic compounds having a terminal phenol group in a structure which contains at least one additional ring and with a molecular weight which is less than 1000 Daltons.
U.S. Pat. No. 5,854,215 describes a method to inhibit the aggregation of natural xcex2-amyloid peptides, including exposing the natural xcex2-amyloid peptide to modulating compounds such that the aggregation of the xcex2-amyloid peptide can be inhibited. The modulating compounds are xcex2-amyloid peptides which have been modified on their amino terminal group.
U.S. Pat. No. 5,840,294 describes a method for the inhibition of amyloid deposition, the method including administering a compound containing an anionic sulfonate group in an amount sufficient to inhibit the interaction between an amyloidogenic protein and a basal membrane constituent. The carrier molecule to which the anionic sulfonate group is attached can be a polymer, a peptide, a peptidomimetic, an aliphatic group, a cycloalkyl group, a heterocyclic group or some combination.
The publications WO 97/16191 and WO 97/16194 relate to the inhibition of amyloid aggregation in mammals via the administration of naphthylazo or 9-acridinone derivatives.
There is currently no specific treatment available for amyloidogenic diseases involving clinically approved drugs that inhibit the formation or development of existing amyloid deposits, or that cause the dissolution of existing amyloid deposits.
After clinical diagnosis of the disease, patients are usually submitted to treatments that are directed towards some of the symptoms associated with the disease. These treatments include, among others, the administration of acetylcholinesterase inhibitors, which act to raise the concentration of the neurotransmitter acetylcholine. Acetylcholine is present at reduced levels in patients with Alzheimer""s disease. Other forms of treatment include the use of anti-oxidants, such as vitamins A, C and E, in an attempt to improve the anti-oxidant properties of the neurons.
There appear to be several pre-requisites for amyloidogenesis in vivo (Kisilevsky, Nature Medicine, 4(7), 772-773, 1998). These include: minimal concentrations of protein or peptide precursor; the presence of a seed or aggregation nucleus; additional components which bind to the amyloid peptide; self-interaction of amyloid peptides and/or interaction with other molecules; and failure of particular amyloid deposit removal mechanisms. The inhibition of the proteolytic processing of the amyloid protein precursor giving rise to the xcex2-amyloid peptide might lead to a reduction in the amyloid peptide concentration, and has been proposed as a possible therapeutic strategy (Higaki et al., J. Neurochem., 68(1), 333-6, 1997; Xu, H. et al., Nature Medicine, 4(4), 447-451, 1998).
Soto et al. (Nature Medicine, 4(7), 882-6, 1998) have proposed the use of peptides which destabilize xcex2-sheets as anti-fiber forming agents and blockers of the in vitro neurotoxicity of Axcex2. The principal problems with the use of peptides as potential therapeutic agents for Alzheimer""s disease arise from the fact that peptides are targets for proteolytic degradation and, as a general rule, present low permeability across the blood-brain barrier. These difficulties therefore limit their pharmaceutical applications.
Therefore, as can be seen from the state of the art, no specific treatment for amyloidogenic diseases exists. The therapeutic approaches include, for example, methods for improving cholinergic transmission, the use of antioxidants, and attempts to administer trophic factors.
None of the approaches presented up to this point directly attacks or has any effect on the molecular causes of the disease, i.e., the formation of amyloid deposits and amyloid plaques.
A method for the inhibition of amyloidoses by administering particular compounds is disclosed herein. More specifically, a method for the treatment and diagnosis of diseases caused by amyloidoses, particularly Alzheimer""s disease, is disclosed, as well as pharmaceutical compositions for inhibition of amyloidoses.
According to the invention particular compounds impede the aggregation of amyloid fibers composed of the xcex2-amyloid peptide, and impede the in vitro neurotoxicity of the xcex2-amyloid peptide or of fibers composed of this peptide. Furthermore, with the aid of a model system of cerebral amyloid deposition, it is shown that aromatic and heteroaromatic compounds as described herein can cause a marked reduction in the volume occupied by amyloid deposits, for example, in the hippocampi of rats.
In one aspect, a method for the treatment and/or prevention of amyloidogenic diseases employing particular compounds is presented.
In another aspect, a pharmaceutical composition for use in individuals suffering from amyloidogenic diseases, particularly Alzheimer""s disease, employing particular compounds is presented.
In yet another aspect, a useful compound to be employed in the development of a pharmaceutical composition for use in individuals suffering from amyloidogenic diseases, particularly Alzheimer""s disease, is presented.
In yet still another aspect, a method to diagnose the deposition of amyloid aggregates, and, consequently, detect pathological conditions associated with amyloid aggregation, such as Alzheimer""s disease, is presented.
As used herein, xe2x80x9camyloidxe2x80x9d refers to extracellular protein deposits that are found in a series of different diseases. As used herein, the term xe2x80x9ctherapeutically effectivexe2x80x9d means that quantity of the aromatic or heteroaromatic compounds described herein which inhibit amyloidosis without causing unacceptable toxic effects. As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d includes an ingredient which is compatible with, and stable when in the presence of, the aromatic or heteroaromatic compounds described herein, and is employed in oral or parenteral formulation, for example, for the intravenous or intramuscular administration of the composition.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entireties. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only, and not intended to be limiting.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.